tbuckley/cabot-search huggingface dataset:
Lysyl hydroxylase PLOD1 enhances actin network to promote confined migration of hepatocellular carcinoma cells via binding with Septin2.
Authors: Zihan Yang, Zhi-hang Zhou, Mengsu Yang
Journal: Journal of Clinical Oncology (2022)

e16111 Background: Hepatocellular carcinoma (HCC) is one of the most lethal cancers due to metastasis. Liver cirrhosis increases tumor stiffness and forms confine space for HCC cells. How HCC cells overcome the confined space to evade is largely unknown. Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase (PLOD) family members, mainly responsible for lysyl hydroxylation, play important roles in tumor progression. The role of PLOD1 in confine migration remains unclear. Methods: LC-MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissues. Microfluidic confine migration device with 6μm high channels was designed to mimic the in vivo confined space. Real-time microscope was used to monitor cell migration. The high throughput 3D invasion assays using Matrigel and Collagen I mixture added to adherent cells was applied to evaluate 3D invasion with high content screening instrument. 3D spheroid formation assays developed by different substitution percentage GelMA created various stiffness environment. IP was performed to pull down the PLOD1-binding proteins. IF staining, Western blot, FRAP, and others were used to evaluate the target expression and cellular phenotype. Results: LC-MS analysis showed that PLOD1 is highly expressed in HCC tissues. High PLOD1 expression level was associated with advanced tumor stage and unfavorable prognosis in 130 HCC patients. We found that confine migration was enhanced by PLOD1 overexpression. With the PLOD1 knockdown or inhibition, the migration speed significantly decreased. Transwell migration also showed PLOD1-overexpressed cell line can migrate faster. 3D invasion and spheroid formation assays also supports the previous findings on chip that PLOD1-overexpressed cells can invade further and generate more spheroids under high stiffness. IP-MS analysis showed that PLOD1 could bind to actin related proteins, including Septin2 (SEPT2). We found that PLOD1 can promote the formation of F-actin network, Septin network and actin polymerization. In addition, knockdown of SEPT2 was able to reverse the effect of PLOD1 on confine migration and inhibited the formation of F-actin network. Co-IP experiments showed that SEPT2 can bind to α-actin. We further found that PLOD1 could promote the binding between SEPT2 and other Septin members. Mechanically, we found that PLOD1 can increase the hydroxylation of SEPT2 protein stabilize it. Finally, orthotopic transplantation assay showed that PLOD1 promoted intrahepatic or extrahepatic metastasis. Conclusions: We demonstrated that PLOD1 increased SEPT2 stability by modifying its hydroxylation, thereby promoting the formation of Septin and F-actin networks, which in turn promotes the confined migration of HCC cells. The current work revealed novel molecular mechanism of PLOD1 on HCC confine migration and metastasis.
External validation of the Bladder Cancer Research Consortium (BCRC) nomogram for predicting survival after radical cystectomy
Authors: N. Corsi, I. Rakic, K. Ginsburg, M. Jamil, A. Sood, D. Dalela, A. Piontkowski, S.E. Majdalany, C. Rogers, F. Abdollah
Journal: European Urology (2022)
HGG-39. Integrative analyses of BRAFp.v600e mutated gliomas: from epigenetic to metabolic characteristics
Authors: Benoit Lhermitte, Thibault Wolf, Izzie Jacques Namer, Caroline Bund, Quentin Fuchs, Monique Dontenwill, Natacha Entz-Werlé
Journal: Neuro-Oncology (2022)

Abstract BRAF p.v600e mutation is encountered in brain tumors, mostly low grade pediatric diffuse gliomas (LGG) and epileptogenic glioneuronal tumors such as gangliogliomas (GG) or pleomorphic xanthoastrocytomas (PXA). Less frequently this mutation is present in high grade glial or glioneuronal tumors such as pleomorphic xanthoastrocytomas with anaplasia, anaplastic ganglioglioma, anaplastic diffuse astrocytomas or glioblastomas. Recently, few publications were highlighting differently the impact of BRAF mutation and CDKN2A deletion, as independent prognostic factors linked to a worst outcome in low grade forms. We studied retrospectively a monocentric cohort of 17 LGGs (14 GG and 3 pilocytic astrocytomas) and 7 BRAF pv600e HGG. The patients were aged below 20 years. We focused on extended tumors’ biology assessment (MethylEpic 850K, Next-Generation sequencing, RNA sequencing and metabolomics), as well as tumor immune microenvironment by immunohistochemistry. Among the LGGs, only one had a CDKN2A deletion and one a gain on chromosome 5. All except two LGGs had a complete surgical resection. Four of them were treated by chemotherapies but underwent relapses. All HGGs had a surgical resection followed by a first line chemotherapy (mainly Stupp protocol) and radiotherapy. Five patients relapsed rapidly, benefiting from targeted therapy with vemurafenib and/or biotherapy associating dabrafenib plus trametinib. Among those HGGs, we had both subgroups: “de novo” tumors and patients with a history of LGG tumors. Both were responding well to targeted treatments. The biology uncovers in all HGGs a loss of CDKN2A gene and/or protein. Additionally to this gene abnormality, specific transcriptomic expressions were associated to therapeutic response and immune microenvironment. Epigenetic modulation was linked to specific metabolic switches when BRAF p.v600e gliomas were getting higher grade features (e.g., glutaminolysis, serinolysis and phospholipidic metabolism). Those characteristics seem to be able to predict in LGG p.v600e potential evolution.
Feasibility and acceptability of measuring psychosocial outcomes for primary brain tumor patients and caregivers in a neuro-oncology clinical setting.
Authors: Anjelica Body, Alayna Ernster, Rebecca Quinones, Phuong Deleyrolle, David Dinh Tran, Maryam Rahman, Deborah Sampson, Jennifer St. Clair, Ashley Parham Ghiaseddin, Deidre B. Pereira
Journal: Journal of Clinical Oncology (2022)

e24131 Background: A primary brain tumor (PBT) is a distressing diagnosis that impacts the psychosocial well-being of patients and caregivers. Validated questionnaires are useful to assess PBT patient and caregiver psychosocial outcomes. However, it is unknown whether it is feasible to assess these outcomes in a routine clinical setting. This study evaluated the feasibility of assessing psychosocial outcomes for PBT patients and caregivers at the UF Health Neuro-Oncology clinic. Methods: 171 participants (100 PBT patients, 75 with malignant glioma; 71 caregivers) completed a battery of questionnaires to assess psychosocial outcomes during routine clinical appointments. At the end of the battery, a Participant Experience Form (PEF) assessed participant perceptions about the overall experience of completing the battery on a 7-point Likert Scale. Based on criteria from Bowen and colleagues (2009), feasibility and acceptability of assessment procedures were conceptualized and operationalized by assessing: Acceptability (80% of participants will have an average score ≥ 4 on the PEF); Practicality (average time of completion will be &lt; 35 minutes); and Implementation (80% of participants will complete the entire battery). Descriptive statistics were used to assess these outcomes. Results: Patient and caregiver scores of feasibility and acceptability outcomes were as follows: Acceptability (Average PEF score: patients = 5.75 [ SD= 0.95]; caregivers = 5.96 [ SD= 0.83]); Practicality (Average time to complete (minutes): patients = 28.7 [ SD= 11.68]; caregivers = 26.0 [ SD= 12.01]); Implementation (% of participants that completed entire battery: patients = 88.0; caregivers = 84.5). Conclusions: The results indicate that assessing psychosocial outcomes in a routine clinical setting for PBT patients and caregivers was feasible, acceptable, and practical. Future research will use this battery to evaluate longitudinal psychosocial outcomes for this population in a clinical setting.
Gastrointestinal melanoma: Outcomes of surgery and immunotherapy.
Authors: Sarah Mazal, Maleka Najmi, Maria Ahmad, Katherine Aguirre, Sherif Elhanafi, Alexander Philipovskiy, Sumit Gaur, Ioannis Konstantinidis
Journal: Journal of Clinical Oncology (2022)

e16224 Background: Most knowledge on gastrointestinal (GI) melanoma is limited to anal melanoma. Our aim is to examine the impact of surgical treatment and the utility of immunotherapy on GI (other than anal) melanoma. Methods: The National Cancer Database (2004-2016) was reviewed for patients who were treated for GI melanoma. Kaplan-Meier method and log-rank test were used to make survival comparisons. Results: We analyzed data from 731 patients with gastrointestinal melanoma (esophageal:97, gastric:57, small bowel:87, colonic:31, rectal:459). A minority of patients had metastatic disease at the time of diagnosis (esophageal:14.4%, gastric:17.5%, small bowel:4.6%, colonic:19.4%, rectal: 16.3%) and small proportion received immunotherapy (esophageal:16.5%, gastric:15.8%, small bowel:15%, colonic:6.5%, rectal:20.3%). Patients who had resection with negative margins had an improved survival irrespectively of the magnitude of surgery (for example rectal melanoma: OS: no surgery:7.9mo, local excision:23.3mo, partial proctectomy:23.5mo, total proctectomy:18.4mo; p &lt; 0.001 and OS for R0 margins:29.4mo vs R1:13.5mo vs R2:5mo;p &lt; 0.001). The use of immunotherapy was associated with improved survival in metastatic disease for rectal melanoma (OS:10.8mo vs 5.7mo; p = 0.01). Conclusions: Excision with negative margins is associated with improved outcomes in gastrointestinal melanoma. The use of immunotherapy should be considered in the presence of metastatic disease.
Randomized, phase 3 study of second-line tislelizumab vs chemotherapy in advanced or metastatic esophageal squamous cell carcinoma, RATIONALE 302: Asia subgroup.
Authors: Kuaile Zhao, Sung-Bae Kim, Ken Kato, Chih-Hung Hsu, Sheng Hu, Feng Wang, Takashi Kojima, Young Saing Kim, Eric Van Cutsem, Jaffer A. Ajani, Liyun Li, Ningning Ding, Aiyang Tao, Lin Shen
Journal: Journal of Clinical Oncology (2022)

e16107 Background: In the global Phase 3 study RATIONALE 302 (NCT03430843), tislelizumab (TIS) demonstrated statistically and clinically significant improvement in overall survival (OS) vs chemotherapy (chemo) (median OS 8.6 vs 6.3 months; HR 0.70; 95% CI 0.57, 0.85; p=0.0001) in patients with advanced or metastatic ESCC. Here, we report data from the Asia subgroup. Methods: Eligible patients who had disease progression after first-line systemic therapy were randomized 1:1 to receive TIS 200 mg intravenously once every three weeks or chemo (paclitaxel, docetaxel, or irinotecan) until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was OS in all randomized patients (intent-to-treat population). The key secondary endpoint was OS in patients with PD-L1 Tumor Area Positivity Score* ≥ 10%; other secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), health-related quality of life, and safety. Results: Of the 512 randomized patients, 404 (79%) were enrolled from China, Taiwan, Japan, and Korea and constituted the Asia subgroup (n=201 TIS, n=203 chemo). At data cut-off (December 1, 2020), median follow-up was 6.9 months in the Asia subgroup. Median OS was 8.5 months with TIS vs 6.3 months with chemo (HR 0.73; 95% CI 0.59, 0.90). Median PFS was 1.5 months with TIS vs 1.7 months with chemo (HR 0.81; 95% CI 0.64, 1.02). TIS resulted in a higher ORR (20.4% [95% CI 15.1, 26.6] vs 9.4% [95% CI 5.7, 14.2]) and longer median DoR (7.4 vs 4.0 months; HR 0.42; 95% CI 0.21, 0.84) vs chemo. In the safety analysis set (n=201 TIS, n=191 chemo), patients treated with TIS had fewer treatment-related adverse events (TRAEs) (74.1% vs 95.3%), fewer ≥ Grade 3 TRAEs (19.4% vs 57.1%), fewer serious TRAEs (15.4% vs 20.9%), and a similar incidence of TRAEs leading to death (2.5% vs 2.6%) vs chemo. Conclusions: In the Asia subgroup, TIS improved OS and tumor response vs chemo as second-line treatment in patients with advanced or metastatic ESCC and showed a well-tolerated safety profile. These findings were consistent with published results in the overall population. *The TAP score methodology has been previously referred to as visually-estimated combined positive score (vCPS) and was previously presented at the American Society of Clinical Oncology 2021, June 4–8, 2021, ESMO World Gastrointestinal Congress 2021, June 30–July 3, 2021, and The Chinese Society of Clinical Oncology 2021, September 25–29, 2021. Clinical trial information: NCT03430843.
LINC-16. Factors Associated with Delayed Diagnosis Among Filipino Pediatric Brain Tumor Patients: A Retrospective Review
Authors: Patricia Orduña, Cheryl Anne Lubaton-Sacro
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Delayed diagnosis is observed greatest among pediatric brain tumors compared to other childhood malignancies. Several factors have been found to influence delay. OBJECTIVE: To determine delayed diagnosis measured by the prediagnostic symptomatic interval (PSI) among Filipino pediatric brain tumor patients and identify associated factors. METHODS: Data was collected retrospectively on pediatric brain tumor patients of Philippine General Hospital from 2015-2019. PSI was calculated. Demographic and clinical data were presented using descriptive statistics. Bivariate and linear regression analyses were used to determine factors. RESULTS: The median overall PSI was 80.5days. The median interval from symptom onset to first physician consult was 22days. The median interval from first consult to subspecialty referral was 23.5days. Majority presented with 2 symptoms at onset (42.3%) and during first physician consult (36.2%). Upon subspecialist referral, 52% have ≥4 symptoms. Most patients (68.4%) consulted with a pediatrician. Most were diagnosed with another condition prior to brain tumor diagnosis. Longer PSI was significantly associated with older age (p=0.005), tumor location (p=0.009), tumor grade (p&amp;lt;0.001), and more physicians consulted prior to subspecialist referral (p=0.001). Significant predictors of delayed diagnosis were supratentorial tumors (4-month delay, p=0.014), and those presenting with seizures (11-month delay, p=0.002), poor school performance (1-year delay, p=0.008), behavioral changes (1.3-year delay, p=0.033), and secondary amenorrhea (3-year delay, p=0.021). Predictors of earlier brain tumor diagnosis include posterior fossa tumors (p=0.041), malignant tumors (p=0.002), and vomiting (p=0.020). CONCLUSION: Delayed diagnosis among Filipino brain tumor patients is associated with age, tumor characteristics and symptoms that are uncommon in this condition. This emphasizes the need for first contact physicians to be aware about these symptoms, and keep a diagnosis of brain tumor as a differential. This, coupled with a detailed history, accurate neurologic examination and early subspecialist referral may lead to earlier diagnosis and treatment for pediatric brain tumor patients.
Outcomes of cirrhotic patients with pre-capillary pulmonary hypertension and pulmonary vascular resistance between 2 and 3 Wood Units
Authors: Marie Caroline Certain, Audrey Baron, Matthieu Turpin, Nathan Ebstein, Athénaïs Boucly, Antoine Beurnier, Mitja Jevnikar, Anne Roche, Sophia Keddache, Sophie Bulifon, Andrei Seferian, Xavier Jaïs, David Montani, Marc Humbert, Olivier Sitbon, Laurent Savale
Journal: European Respiratory Journal (2022)

<b>Pulmonary vascular resistance between 2 and 3 Wood Units in patients with portal hypertension and pre-capillary pulmonary hypertension could characterise early portopulmonary hypertension with clinical consequences</b> https://bit.ly/3PEFe79
Outcomes of combined ipilimumab/nivolumab in metastatic uveal melanoma: A prevalence meta-analysis.
Authors: Ceren Durer, Seren Durer, Gilles Jad Hoilat, Ahmed Abu-Zaid, Mohammed M. Milhem
Journal: Journal of Clinical Oncology (2022)

9534 Background: Uveal melanoma is the most common primary intraocular malignant tumor in adults and, approximately 40-50% of the patients eventually develop metastatic disease. Metastatic uveal melanoma has a dismal prognosis with an overall survival of &lt; 50% at 1-year. Single-agent check point inhibitors revealed minimal benefit and novel approaches are underway to improve the outcomes with the recent approval of Tebentafusp in uveal melanoma. The purpose of this metanalysis was to assess the safety and efficacy of combined immunotherapy with ipilimumab (3 mg/kg x q3w for 4 cycles) and nivolumab (1 mg/kg x q3w for 4 cycles) in metastatic uveal melanoma. Methods: A comprehensive literature search on PubMed, Embase, Cochrane and Web of Science was conducted. Two independent reviewers screened the literature and extracted data. Our search strategy included MeSH terms and key words for metastatic uveal melanoma; ipilimumab and nivolumab. OpenMeta[Analyst] software was used for the analysis. The endpoints included the prevalence of overall response rate (ORR), complete response (CR), ≥grade-III diarrhea/colitis, and ≥grade-III hepatic toxicity. Additional endpoint included the median overall survival (OS) was reported as a range. Random-effects model (DerSimonian-Laird method) was applied. Results: Overall, eight studies (n = 379) were included for the analysis. Five studies were phase II, three studies were retrospective. 52% of the patients were male with good performance status. Median follow-up ranged from 9.2 mo-28 mo. 40% of the patients (n = 142) had elevated LDH at the time of treatment. GNAQ and GNA11 mutations were reported in three studies, BRAF mutation was reported in two studies. The pooled prevalence for ORR was 13.7% (95% CI: 9.2–18.2%, N = 6 studies, n = 33/226) with CR of 2.1% (95% CI: 0.3–3.9%, N = 6 studies, n = 8/226). The median OS ranged from 12.7 to 19.1 months (N = 7 studies). Majority of the patients experienced treatment-related adverse events. Most common side effects included diarrhea, colitis, hepatic toxicities, skin disorders, hypothyroidism. The pooled prevalence for ≥grade III hepatic toxicity was 26.2% (95% CI: 13.9–0.385%, N = 5 studies, n = 60/219). Conclusions: Combined checkpoint blockade with ipilimumab and nivolumab showed an ORR of 13.7% which appears to show better clinical activity than single-agent checkpoint inhibitor. Most common treatment side effect was hepatic toxicity.
Mismatch Repair-Deficient Colorectal Cancer: Building on Checkpoint Blockade
Authors: Zhaohui Jin, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2022)

Colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) is characterized by hypermutation leading to abundant neoantigens that activate an antitumor immune response in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) have transformed the treatment of this subset of CRC and other solid tumors with dMMR, by producing frequent and durable responses that extend patient survival. Recently, the anti-programmed death-1 (PD-1) antibody pembrolizumab was shown to produce significantly longer progression-free survival with fewer adverse events compared with chemotherapy as first-line treatment of metastatic CRC (mCRC) with dMMR. Accordingly, single-agent pembrolizumab represents a new standard of care for dMMR mCRCs including patients with Lynch syndrome and the more common sporadic cases. Furthermore, data indicate that the combination of PD-1 and cytotoxic T-cell lymphocyte-4 inhibitors was more effective than single-agent PD-1 inhibition in patients with dMMR mCRCs, suggesting nonredundant mechanisms of action. Although the benefit of ICIs is currently limited to metastatic disease, studies evaluating ICIs as neoadjuvant and adjuvant therapy in earlier-stage dMMR CRC are ongoing. Despite success of ICIs in the treatment of metastatic dMMR cancers, an appreciable proportion of these tumors demonstrate intrinsic or acquired resistance, and biomarkers to identify these patients are needed. Advances in the understanding of immunotherapy resistance mechanisms hold promise for both biomarker identification and development of novel strategies to circumvent treatment resistance. In this review, we present a comprehensive overview of the evidence for the role of immunotherapy in the treatment of dMMR CRC, discuss resistance mechanisms, and outline potential strategies to circumvent primary and secondary resistance with the goal of broadening the benefit of ICIs.
A pooled analysis of surufatinib safety from phase 3 trials in advanced NETs.
Authors: Jie Li, Jianming Xu, Lin Shen, Chunmei Bai, Zhiwei Zhou, Zhiping Li, Yihebali Chi, Xianjun Yu, Enxiao LI, Nong Xu, Tianshu Liu, Wenhui Lou, Yuxian Bai, Xianglin Yuan, Xiuwen Wang, Ying Yuan, Jia Chen, Tao Zhang, Dianrong Xiu, Weiguo Su
Journal: Journal of Clinical Oncology (2022)

4126 Background: Surufatinib is a small-molecule inhibitor of VEGFR1, 2, &amp; 3, FGFR1, and CSF-1R. Surufatinib demonstrated prolonged PFS and tolerable safety in two phase 3 studies in advanced neuroendocrine tumors (NETs) of pancreatic (SANET-p; NCT02589821) and extrapancreatic (SANET-ep; NCT02588170) origin (Xu, 2020 Lancet Oncology). Detailed outcomes on safety from these 2 studies are reported here as a pooled analysis. Methods: Data is pooled from SANET-p and SANET-ep studies which have similar designs including a 2:1 randomization of surufatinib to placebo in patients ≥18 years with advanced, well differentiated NETs, progressing on or after ≤2 prior therapies. Surufatinib 300 mg or placebo, was administered once daily until disease progression or unacceptable toxicity. Safety outcomes for each pooled treatment group are reported as treatment-emergent adverse events (TEAE) assessed by NCI-CTC 4.03. Patients were included if they had received study treatment during the double-blinded phase of the studies. Results: As of 30 th June 2020, 396 patients were assigned to the surufatinib (n = 263) and placebo (n = 133) groups. Median treatment duration was longer with surufatinib 7.4 months (range 0.1–41.4) compared with placebo 4.6 months (range 0.1–39.9). 29% of patients reached more than 12 months of treatment with surufatinib group compared to 11% with placebo. The mean relative dose intensity was 87.56% in the surufatinib group and 97.01% in the placebo group. Most common TEAEs (surufatinib vs placebo) were proteinuria 68.8% vs 54.9%, hypertension 68.4% vs 27.1%, and diarrhea 49% vs 22.6%. Most common grade ≥3 TEAE were hypertension 38.8% vs 13.5%, proteinuria 14.8% vs 0.8% and hypertriglyceridaemia 5.3% vs 0%. Deaths due to TEAEs were comparable between groups 2.7% vs 2.3%. TEAEs led to dose reductions in 43.0% vs 6.8% of patients and dose interruptions in 47.1% vs 29.3% of patients. The majority of patients (83.3% vs 93.2%) were managed without discontinuation because of TEAE. Median onset of proteinuria and hypertension were &lt; 1 month in both groups. Median (range) onset was 0.95 months (0.16–30.36) vs 0.95 months (0.23–16.95) for proteinuria and 0.49 months (0.03–31.18) vs 0.89 months (0.03–14.75) for hypertension. Among patients with hypertension, 59% (n = 111) vs 28% (n = 11) received antihypertensive medication. Conclusions: Surufatinib was generally well tolerated in this pooled analysis and the safety profile was consistent with its previously reported data. The monitoring and management of hypertension and proteinuria are important for patients receiving surufatinib. Clinical trial information: NCT02589821; NCT02588170. [Table: see text]